Exp Mol Med.  2004 Jun;36(3):233-242.

Association of DNA-dependent protein kinase with hypoxia induciblefactor-1 and its implication inresistance to anticancer drugs in hypoxic tum or cells

• Um JH
• Kang CD
• Bae JH
• Shin GG
• Kim DW
• Kim DW
• Chung BS
• Kim SH

Abstract

Tumor hypoxia contributes to the progression of a malignant phenotype and resistance to ionizing radiation and anticancer drug therapy. Many of these effects in hypoxic tumor cells are mediated by expression of specific set of genes whose relation to therapy resistance is poorly understood. In this study, we revealed that DNA-dependent protein kinase (DNA-PK), which plays a crucial role in DNA double strand break repair, would be involved in regulation of hypoxia inducible factor-1 (HIF-1). HIF-1beta-deficient cells showed constitutively reduced expression and DNA-binding activity of Ku, the regulatory subunit of DNA-PK. Under hypoxic condition, the expression and activity of DNA- PK were markedly induced with a concurrent increase in HIF-1alpha expression. Our result also demonstrated that DNA-PK could directly interact with HIF- and especially DNA-PKcs, the catalytic subunit of DNA-PK, could be involved in phosphorylation of HIF-1alpha, suggesting the possibility that the enhanced expression of DNA- PK under hypoxic condition might attribute to modulate HIF-1alpha stabilization. Thus, the correlated regulation of DNA-PK with HIF-1 could contribute to therapy resistance in hypoxic tumor cells, and it provides new evidence for developing therapeutic strategies enhancing the efficacy of cancer therapy in hypoxic tumor cells.

Keyword

DNA-PK; drug resistance; HIF-1; hypoxia Introduction

MeSH Terms

Antibodies/immunology
Cell Hypoxia
Cell Line, Tumor
DNA Helicases/immunology/metabolism
DNA-Binding Proteins/genetics/*metabolism/*physiology
Deferoxamine/pharmacology
Drug Resistance, Neoplasm/*physiology
Humans
Immunoprecipitation
Neoplasms/enzymology/*metabolism
Nuclear Proteins/genetics/*metabolism/physiology
Phosphorylation
Protein-Serine-Threonine Kinases/metabolism/*physiology
Research Support, Non-U.S. Gov't
Transcription Factors/genetics/*metabolism/physiology
Up-Regulation